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Superfast muscles power high-frequency motions such as sound production and visual tracking. As a class, these muscles also generate low forces. Using the toadfish swimbladder muscle, the fastest known vertebrate muscle, we examined the crossbridge kinetic rates responsible for high contraction rates and how these might affect force generation. Swimbladder fibers have evolved a 10-fold faster crossbridge detachment rate than fast-twitch locomotory fibers, but surprisingly the crossbridge attachment rate has remained unchanged. These kinetics result in very few crossbridges being attached during contraction of superfast fibers (only ≈ 1/6 of that in locomotory fibers) and thus low force. This imbalance between attachment and detachment rates is likely to be a general mechanism that imposes a tradeoff of force for speed in all superfast fibers.

The pulsatile secretion of luteinizing hormone (LH), occasioned by the pulsatile release of gonadotropin-releasing hormone (GnRH), is closely associated with concurrent increases in multiunit electrical activity in the mediobasal hypothalamus (MUA volleys), the electrophysiological correlates of GnRH pulse generator activity. These volleys represent a highly synchronized increase in firing frequency of individual neurons. The origin of these rhythmic oscillations in unit activity and the mechanisms responsible for their synchronization are unknown. The purpose of the present study was to examine the role, if any, of GnRH in the functioning of the GnRH pulse generator in rhesus monkeys. Ovariectomized animals bearing recording electrodes chronically implanted in the mediobasal hypothalamus and fitted with intracerebro-ventricular (ICV) cannulae in the lateral ventricle and with indwelling cardiac catheters were studied. LH was measured in venous blood withdrawn from the cardiac catheters every 10 min while hypothalamic electrical activity was monitored continuously. In Experiment 1, following a 3- to 4-hour control period, GnRH was infused ICV at a rate of 300 ng/kg body weight (BW)/h over 4-5 h. In Experiment 2, antide, a long-acting GnRH antagonist, was injected ICV in a dose of 105 µg/kg BW after a control period of 3-4 h. Additional control experiments were performed in each animal using vehicle alone. Neither GnRH nor antide affected the frequency of MUA volleys and attendant LH pulses despite significant alterations in LH secretion. These results suggest that, in the rhesus monkey, GnRH may not be involved in the operation of the GnRH pulse generator.

The force production and the adenosine triphosphate (ATP) utilization rates of muscle fibers was measured simultaneously using an apparatus that is not limited by diffusion of substrates unlike conventional fluorometric ATPase equipment. The apparatus consisted of a muscle cuvette chamber and two micro-machined propellers which enables accurate examination of the time course of fluorescence changes of the muscle fibers. It allows no diffusional limitation in its measurement functions.

Comparisons of sonic muscle width, body cavity length, and sonic muscle innervation patterns were made for three species of sciaenids: weakfish, Cynoscion regalis; Atlantic croaker, Micropogonias undulatus; and spot, Leiostomus xanthurus. Body cavity length and sonic muscle width (rostrocaudal extent), both normalized for TL, were significantly different among the three species, increasing from spot to croaker to weakfish. However, the percentage of the body cavity length including sonic muscle was greater in the croaker and weakfish than in the spot. The sonic muscles of sciaenids are innervated by a number of true spinal nerves rather than by paired occipital spinal nerves. The number of sonic nerves increased from spot (4–5 nerves from vertebrae 4–9) to croaker (6–8 from vertebrae 3–10) to weakfish (8–9 nerves from vertebrae 3–12), paralleling the increase in muscle width. Although the number of nerves and their vertebra of origin varied within each species, they were bilaterally symmetrical within an individual. The spinal nerves emerged from two (dorsal and ventral) foramina in croaker and spot and from the sole foramen observed in weakfish vertebrae. Therefore, a longer body cavity supports a wider sonic muscle that is innervated by a greater number of spinal nerves.

Background Depression and dementia are both common diseases. Although new cases of depression are more common in younger adults, there is a second peak at the age of 50 years suggesting a different pathological process. Late-life depression (LLD) is associated with dementia. However, it remains unclear whether depression represents a dementia prodrome or is a true risk factor for its development. LLD is thought to have a vascular component and this may be a possible link between depression and dementia. We hypothesised that later-life depression is a prodromal manifestation of dementia and would therefore be associated with more AD, and/or ischaemic brain abnormalities that are present in earlier-life depression or in age- and sex-matched controls. Methods We assessed post-mortem orbitofrontal cortex and dorsolateral pre-frontal cortex from 145 individuals in 4 groups: 28 18–50-year-olds with depression, 30 older individuals (ages 51–90) with depression, 28 with early AD (Braak tangle stages III–IV) and 57 matched controls (17 early-life, 42 later-life). Levels of Aβ, phospho-tau and α-synuclein were assessed by immunohistochemistry and ELISA. To quantify chronic ischaemia, VEGF, MAG and PLP1 were measured by ELISA. To assess pericyte damage, PDGFRB was measured by ELISA. For blood–brain barrier leakiness, JAM-A, claudin 5 and fibrinogen were measured by ELISA. To quantity endothelial activation, the ratio of ICAM1:collagen IV was assessed by immunohistochemistry. Results There was no evidence of chronic cerebral hypoperfusion or increased Aβ/tau in either depression group. There was also no indication of pericyte damage, increased blood–brain barrier leakiness or endothelial activation in the OFC or DLPFC in the depression groups. Conclusions Contrary to some previous findings, we have not found evidence of impaired vascular function or increased Aβ in LLD. Our study had a relatively small sample size and limitations in the availability of clinical data. These results suggest that depression is a risk factor for dementia rather than an early manifestation of AD or a consequence of cerebral vascular insufficiency.

Chronic kidney disease (CKD) affects 11-13% of the world's population and greatly increases risk of atherosclerotic cardiovascular disease (ASCVD) and death. It is characterized by systemic inflammation and disturbances in the blood leukocytes that remain incompletely understood. In particular, abnormalities in the numbers and relative proportions of the three major monocyte subsets-classical, intermediate, and non-classical-are described in CKD and end-stage renal disease. In this study, we characterized absolute numbers of blood leukocyte subtypes in adults with renal function varying from normal to advanced CKD. The primary aim was to identify monocyte subpopulations that associated most closely with current estimated glomerular filtration rate (eGFR) and subsequent rate of eGFR decline. Leucocyte and monocyte populations were enumerated by multi-color flow cytometry of whole blood and peripheral blood mononuclear cell (PBMC) samples from adults with CKD stage 1-5 ( = 154) and healthy adults ( = 33). Multiple-linear regression analyses were performed to identify associations between numbers of leucocyte and monocyte populations and clinical characteristics including eGFR and rate of eGFR decline with adjustment for age and gender. In whole blood, total monocyte and neutrophil, but not lymphocyte, numbers were higher in adults with CKD 1-5 compared to no CKD and were significantly associated with current eGFR even following correction for age. In PBMC, classical and intermediate monocyte numbers were higher in CKD 1-5 but only intermediate monocyte numbers were significantly associated with current eGFR in an age-corrected analysis. When intermediate monocytes were further sub-divided into those with mid- and high-level expression of class II MHC (HLA-DR and HLA-DR intermediate monocytes) it was found that only DR intermediate monocytes were increased in number in CKD 1-5 compared to no CKD and were significantly associated with eGFR independently of age among the total (No CKD + CKD 1-5) study cohort as well as those with established CKD (CKD 1-5 only). Furthermore, blood number of DR intermediate monocytes alone proved to be significantly associated with subsequent rate of renal functional decline. Together, our data confirm neutrophil and monocyte subset dysregulation in CKD and identify a distinct subpopulation of intermediate monocytes that is associated with higher rate of loss of kidney function.

PurposeTo develop a new lipid-based particle formulation platform for respiratory drug delivery applications. To find processing conditions for high surface rugosity and manufacturability. To assess the applicability of the new formulation method to different lipids.MethodsA new spray drying method with a simplified aqueous suspension feedstock preparation process was developed for the manufacture of rugose lipid particles of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC). A study covering a wide range of feedstock temperatures and outlet temperatures was conducted to optimize the processing conditions. Aerosol performance was characterized in vitro and in silico to assess the feasibility of their use in respiratory drug delivery applications. The applicability of the new spray drying method to longer-chain phospholipids with adjusted spray drying temperatures was also evaluated.ResultsHighly rugose DSPC lipid particles were produced via spray drying with good manufacturability. A feedstock temperature close to, and an outlet temperature lower than, the main phase transition were identified as critical in producing particles with highly rugose surface features. High emitted dose and total lung dose showed promising aerosol performance of the produced particles for use as a drug loading platform for respiratory drug delivery. Two types of longer-chain lipid particles with higher main phase transition temperatures, 1,2-diarachidoyl-sn-glycero-3-phosphocholine (DAPC) and 1,2-dibehenoyl-sn-glycero-3-phosphocholine (22:0 PC), yielded similar rugose morphologies when spray dried at correspondingly higher processing temperatures.ConclusionsRugose lipid particles produced via spray drying from an aqueous suspension feedstock are promising as a formulation platform for respiratory drug delivery applications. The new technique can potentially produce rugose particles using various other lipids.